High purity 2-naphthylacetonitrile and method for producing same

ABSTRACT

High purity 2-naphthylacetonitrile with fewer impurities can be used as a starting material or intermediate for synthesizing various pharmaceutical products, agricultural chemicals, and chemical products, and a production method thereof. A high purity 2-naphthylacetonitrile having an HPLC purity of 2-naphthylacetonitrile of not less than 95 area %, and containing naphthalene compounds represented by the formulas (a)-(j) at a content of a predetermined area % or below. A method for producing high purity 2-naphthylacetonitrile, may include: subjecting 2′-acetonaphthone to a Willgerodt reaction in the presence of an additive where necessary, and hydrolyzing the obtained amide compound to give 2-naphthylacetic acid; and reacting the 2-naphthylacetic acid obtained in the subjecting, a halogenating agent and sulfamide in the presence of a catalyst as necessary in an organic solvent to give 2-naphthylacetonitrile.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is the national stage of internationalapplication PCT/JP2020/040413, filed on Oct. 28, 2020, and claims thebenefit of the filing date of Japanese Application No. 2019-196782,filed on Oct. 29, 2019.

TECHNICAL FIELD

The present invention relates to high purity 2-naphthylacetonitrileuseful as a starting material or intermediate for the synthesis ofvarious pharmaceutical products, agricultural chemicals, chemicalproducts and the like, and a production method thereof.

BACKGROUND ART

2-Naphthylacetonitrile is useful as a starting material for synthesis,or an intermediate for synthesis of various pharmaceutical products,agricultural chemicals, chemical products and the like. In addition, anaromatic nitrile compound having a chemical structure similar to that of2-naphthylacetonitrile is expected to be usable as a starting materialfor synthesis, or an intermediate for synthesis of variouspharmaceutical products, agricultural chemicals, and chemical products.

For example, 2-naphthylacetonitrile is useful as a starting material forsynthesis, or an intermediate for synthesis of pharmaceutical productssuch as pharmaceutical products used for the prophylaxis, treatment andthe like of depression (e.g., major depressive disorder, bipolardisease), fibromyalgia, pain (e.g., neuropathic pain), sleep disorder,attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), restless legs syndrome, schizophrenia, anxiety,obsessive-compulsive disorder, post-traumatic stress disorder, seasonalaffective disorder (SAD), premenstrual dystonia, CNS diseases such asneurodegenerative disease (e.g., Parkinson's disease, Alzheimer'sdisease) and the like, diseases relating to urinary incontinence andirritable bowel syndrome (IBS), diabetes and the like, erythropoietin(EPO) inducer, calcium antagonist, histamine receptor antagonist,tachykinin receptor antagonist, 12-lipoxygenase inhibitor, proteinkinase C (PKC) inhibitor, PDE IV inhibitor and the like.

2-Naphthylacetonitrile can be particularly preferably used as a startingmaterial/intermediate for producing(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane which is apharmaceutical product described in patent document 1, patent document2, patent document 3 and the like.

As a production method of 2-naphthylacetonitrile, a method includingbrominating 2-methylnaphthalene to give 2-(bromomethyl)naphthalene, andreacting same with potassium cyanide (non-patent document 1) is known.

However, this method is not preferable as an industrial productionmethod since the yield is low, many by-products are generated bybromination, highly toxic compounds such as carbon tetrachloride,potassium cyanide and the like are used, and the like.

Furthermore, a method for synthesizing a nitrile compound from aromaticcarboxylic acid, aromatic carboxylic acid derivative and the like hasbeen reported (non-patent document 2).

Non-patent document 2 describes a method including dissolving carboxylicacid halide having various structures such as aromatic ring and the likeand sulfamide in sulfolane, and reacting and converting same to anitrile compound.

In the method of non-patent document 2, however, some substrates showlow yields, and further improvements are desired as an industrialproduction method.

A method for synthesizing aromatic carboxylic acid and aromaticthioamide from aromatic ketone by Willgerodt reaction has been reportedin non-patent document 3.

However, these methods require further improvement as industrialproduction methods since the yield is not sufficient and the resultingaromatic carboxylic acid and the like are considered to contain muchsulfur due to the use of sulfur in Willgerodt reaction.

In addition, 2-naphthylacetonitrile obtained by these methods isconsidered to contain several percents of by-products such as sulfur,amide compound, thioamide compound and the like, inferring from theseproduction methods and the yields thereof.

DOCUMENT LIST Patent Documents

-   patent document 1: WO 2007/016155-   patent document 2: WO 2015/089111-   patent document 3: WO 2015/102826

Non-Patent Documents

-   non-patent document 1: Tetrahedron Letters 56 (2015) 2054-2058-   non-patent document 2: Tetrahedron Letters, Vol. 23, No. 14, pp.    1505-1508, 1982-   non-patent document 3: Synthetic Communications, Vol. 33, No. 1, pp.    59-63, 2003

SUMMARY OF INVENTION Technical Problem

The present invention provides a method for producing high purity2-naphthylacetonitrile which has fewer impurities, and can be producedsafely and highly efficiently on an industrial scale at a low cost.

Solution to Problem

In an attempt to solve the above-mentioned problems, the presentinventors found production of aromatic carboxylic acid compound byWillgerodt rearrangement using comparatively economical and generalaromatic ketone compounds such as 2′-acetonaphthone and the like, andfurther, a method for producing a highly pure aromatic nitrile compoundsuch as 2-naphthylacetonitrile and the like in a high yield from thearomatic carboxylic acid compound (International Application No.PCT/JP2019/018065).

Generally, the starting materials and intermediates for synthesizingpharmaceutical products are required to have high purity so thatunexpected side effects will not be caused by impurities containedtherein. As the impurity, by-products resulting from the production ofthese can be mentioned. By-products may be removed during purificationand production process of the target drug. However, when pharmaceuticalproducts are industrially produced in large amounts, further reductionof production costs and purification costs is desired to achieve stablesupply, suppression of price and the like of the pharmaceuticalproducts. Thus, highly pure starting materials and intermediatescontaining less impurities are desired for synthesizing pharmaceuticalproducts.

The present inventors have studied and found that 2-naphthylacetonitrileobtained by the production method described in the aforementionedinternational application has a lower content of by-products than byconventionally known methods, and reached the present invention.

The present inventors have further studied the production method.

That is, the gist of the present invention is as follows.

[1] A high purity 2-naphthylacetonitrile having an HPLC purity of2-naphthylacetonitrile of not less than 95 area %, comprising one ormore kinds selected from the naphthalene compounds represented by thefollowing formulas (a)-(j) as impurities, wherein a content of eachnaphthalene compound is as follows:

[2] The high purity 2-naphthylacetonitrile of [1], comprising one ormore kinds selected from the naphthalene compounds represented by thefollowing formulas (a)-(d) as impurities, wherein the content of eachnaphthalene compound is as follows:

[3] The high purity 2-naphthylacetonitrile of [1], comprising thenaphthalene compound represented by the following formula (c) asimpurity, wherein the content of the naphthalene compound represented bythe following formula (c) is not more than 1 area %:

[4] A method for producing a high purity 2-naphthylacetonitrile,comprising mixing a reaction starting material 1 comprising an acidhalide compound represented by the following formula (5)

wherein, in the formula (5), X is a halogen atom,and a first organic solvent, and a reaction starting material 2comprising sulfamide and a second organic solvent at 15° C.-90° C.,raising the temperature and reacting the mixture at 80° C.-180° C. togive 2-naphthylacetonitrile.[5] The production method of [4], wherein the reaction starting material1 is added to the reaction starting material 2 at 15° C.-90° C., thetemperature is raised, and the mixture is reacted at 80° C.-180° C.[6] The production method of [5], wherein the reaction starting material1 is added to the reaction starting material 2 such that the amount ofthe acid halide compound represented by the aforementioned formula (5)

is not less than 0.0027 mol/min per 1 mol of sulfamide.[7] The production method of any one of [4] to [6], wherein the reactionstarting material 1 is obtained by mixing 2-naphthylacetic acid, ahalogenating agent and the first organic solvent in the presence of acatalyst where necessary.[8] A method for producing high purity 2-naphthylacetonitrile,comprising the following step 1 and step 2:step 1:

a step of subjecting 2′-acetonaphthone to a Willgerodt reaction in thepresence of an additive where necessary, hydrolyzing the obtained amidecompound, and liberating 2-naphthylacetic acid to give 2-naphthylaceticacid;

step 2:

a step of mixing and reacting a reaction starting material 1 comprisingthe 2-naphthylacetic acid obtained in step 1, a halogenating agent and afirst organic solvent, and a reaction starting material 2 comprisingsulfamide and a second organic solvent to give 2-naphthylacetonitrile.

[9] The production method of any one of [4] to [7], wherein the firstorganic solvent is a hydrocarbon solvent, an amide solvent, a sulfonesolvent or a mixed solvent thereof, and the second organic solvent is asulfone solvent.

In addition, the present invention relates to the following.

[1A] A high purity 2-naphthylacetonitrile having an HPLC purity of2-naphthylacetonitrile of not less than 95 area %, and comprisingnaphthalene compounds represented by the following formulas (a)-(i) atthe following contents:

[2A] A method for producing a high purity 2-naphthylacetonitrile,comprising the following step 1A and step 2A:step 1A:

a step of subjecting 2′-acetonaphthone to a Willgerodt reaction in thepresence of an additive where necessary, hydrolyzing the obtained amidecompound, and neutralizing same to give 2-naphthylacetic acid;

step 2A:

a step of reacting the 2-naphthylacetic acid obtained in step 1A, ahalogenating agent and a compound represented by the following formula(7)R¹SO₂R²  (7)wherein R¹ and R² are each independently a chlorine atom, a hydroxylgroup, an amino group, an isocyanate group or a p-tolyl group,in the presence of a catalyst as necessary in an organic solvent to give2-naphthylacetonitrile.[3A] The production method of [2A], wherein the aforementioned step 2Ais a step of mixing and reacting a reaction starting material 1 which isa mixture of the 2-naphthylacetic acid obtained in step 1A, ahalogenating agent, a first organic solvent and, where necessary, acatalyst, with a reaction starting material 2 which is a mixture of acompound represented by the aforementioned formula (7) and a secondorganic solvent to give 2-naphthylacetonitrile.[4A] The production method of [3A], wherein the first organic solvent isa hydrocarbon solvent, a sulfone solvent or a mixture of these, and thesecond organic solvent is a sulfone solvent.[5A] The production method of [3A], wherein the aforementioned step 2Ais a step of mixing a reaction starting material 1 which is a mixture ofthe 2-naphthylacetic acid obtained in step 1A, a halogenating agent, afirst organic solvent and, where necessary, a catalyst, with a reactionstarting material 2 which is a mixture of a compound represented by theaforementioned formula (7) and a second organic solvent at 15° C.-90°C., raising the temperature and reacting the mixture at 80° C.-180° C.to give 2-naphthylacetonitrile.[6A] The production method of [3A], wherein the aforementioned step 2Ais a step of adding a reaction starting material 1 which is a mixture ofthe 2-naphthylacetic acid obtained in step 1A, a halogenating agent, afirst organic solvent and, where necessary, a catalyst, to a reactionstarting material 2 which is a mixture of a compound represented by theaforementioned formula (7) and a second organic solvent and reacting themixture to give 2-naphthylacetonitrile, wherein the reaction startingmaterial 1 is added to the reaction starting material 2 such that theamount of an acid halide compound represented by the following formula(5)

wherein, in the formula (5), X is a halogen atom,contained in the reaction starting material 1 is not less than 0.0027mol/min per 1 mol of the compound represented by the aforementionedformula (7) contained in the reaction starting material 2.[7A] The production method of [2A], wherein, after the aforementionedhydrolysis in the aforementioned step 1A, the reaction product obtainedby the hydrolysis is contacted with a hydrocarbon solvent; a hydrocarbonsolvent is present during the aforementioned neutralization; or thereaction product obtained by the aforementioned neutralization iscontacted with a hydrocarbon solvent.

Advantageous Effects of Invention

According to the present invention, high purity 2-naphthylacetonitrilewith less impurity which is useful as a starting material orintermediate for the synthesis of various pharmaceutical products,agricultural chemicals, and chemical products, particularly a startingmaterial or intermediate for the synthesis of pharmaceutical products,can be provided. In addition, a production method capable of producinghigh purity 2-naphthylacetonitrile safely, highly efficiently,industrially in a large amount at a low cost can be provided.Furthermore, using the 2-naphthylacetonitrile of the present invention,pharmaceutical products such as(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane and the like canbe produced industrially in a large amount at a low cost.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the HPLC analysis results of 2-naphthylacetonitrileobtained in Example 1.

FIG. 2 shows the HPLC analysis results of 2-naphthylacetonitrileobtained in Example 3.

DESCRIPTION OF EMBODIMENTS

The present invention is described in detail below.

High Purity 2-Naphthylacetonitrile of the Present Invention

The high purity 2-naphthylacetonitrile of the present invention showslower contents of specific by-products (impurities) than before. To bespecific, an HPLC purity of 2-naphthylacetonitrile is not less than 95area %, and the contents of the naphthalene compounds represented by thefollowing formulas (a)-(j) are as shown in Table 1.

TABLE 1 (a)

not more than 0.3 area % (b)

not more than 0.1 area % (c)

not more than 1 area % (d)

not more than 0.1 area % (e)

not more than 0.05 area % (f)

not more than 0.05 area % (g)

not more than 0.1 area % (h)

not more than 0.05 area % (i)

not more than 0.05 area % (j)

not more than 0.05 area %

The compounds represented by the above-mentioned formulas (a), (b), (c),(d) and (h) are impurities that are difficult to remove by purificationoperations such as solid-liquid separation by crystallization, columnpurification and the like, and it is preferable to suppress theproduction amount thereof from the aspects of quality and purificationcost.

The compounds represented by the above-mentioned formulas (e), (f), (g),(i) and (j) have high reactivity and sometimes cause side reactions.Thus, it is preferable to prevent them from remaining in2-naphthylacetonitrile.

The HPLC purity of the high purity 2-naphthylacetonitrile of the presentinvention is preferably not less than 97 area %, more preferably notless than 98 area %, particularly preferably not less than 99 area %.

The content of the naphthalene compound represented by theabove-mentioned formula (a) is preferably not more than 0.25 area %,more preferably not more than 0.2 area %, further preferably not morethan 0.15 area %, particularly preferably not more than 0.1 area %.

The content of each of the naphthalene compounds represented by theabove-mentioned formulas (b) and (d) is preferably not more than 0.08area %, more preferably not more than 0.05 area %, further preferablynot more than 0.03 area %, particularly preferably not more than 0.01area %.

The content of the naphthalene compound represented by theabove-mentioned formula (c) is preferably not more than 0.8 area %, morepreferably not more than 0.5 area %, further preferably not more than0.3 area %, particularly preferably not more than 0.1 area %.

The content of each of the naphthalene compounds represented by theabove-mentioned formulas (e), (f) and (h) is preferably not more than0.03 area %, more preferably not more than 0.02 area %, furtherpreferably not more than 0.01 area %, particularly preferably not morethan 0.005 area %.

The content of the naphthalene compound represented by theabove-mentioned formula (g) is preferably not more than 0.08 area %,more preferably not more than 0.05 area %, further preferably not morethan 0.03 area %, particularly preferably not more than 0.01 area %.

The content of each of the naphthalene compounds represented by theabove-mentioned formulas (i) and (j) is preferably not more than 0.03area %, more preferably not more than 0.02 area %, further preferablynot more than 0.01 area %, particularly preferably 0 area %.

The content of the naphthalene compound represented by the followingformula is preferably not more than 0.08 area %, more preferably notmore than 0.05 area %, further preferably not more than 0.03 area %,particularly preferably not more than 0.01 area %:

The high purity 2-naphthylacetonitrile of the present invention has asmall content of impurities and can be sufficiently used as it is as astarting material or intermediate for the synthesis of pharmaceuticalproducts even without a purification operation or the like. Therefore,it is useful as a starting material or intermediate for the synthesis ofpharmaceutical products.

The production method of the present invention to be described later cansuppress production of the naphthalene compound represented by theabove-mentioned formula (c) which has the highest content among theimpurities in the high purity 2-naphthylacetonitrile of the presentinvention.

The relative retention time (RRT) of the naphthalene compoundsrepresented by the above-mentioned formulas (a)-(h) is as shown in Table2. The relative retention time may vary by about ±0.05 due to the HPLCmeasurement conditions.

TABLE 2 naphthalene compound RRT 2-naphthylacetonitrile 1.00 (a) 1.08(b) 1.22 (c) 1.35 (d) 1.57 (e) 0.49 (f) 0.58 (g) 1.22 (h) 1.40

In the present invention, the purity and the content of impurity of2-naphthylacetonitrile can be measured by the peak area ratio in highperformance liquid chromatography (HPLC) which is a method well known inthe field of analysis chemistry. The measurement conditions of HPLC canbe appropriately selected, and the conditions shown below are preferred.

analysis instrument: HPLC (1200 series) manufactured by Agilent

column: Zorbax Eclipse Plus Phenyl-Hexyl, 5 μm, 250 mm×4.6 mm

mobile phase A: 0.1 volume % trifluoroacetic acid aqueous solution

mobile phase B: acetonitrile

gradient: 0 min (B:30%)−15 min (B:60%)−20 min (B:95%)−30 min (B:95%)

flow rate: 1.0 mL/min

injection volume: 5 μL

detection wavelength: 280 nm

column temperature: 40° C.

The color tone of the high purity 2-naphthylacetonitrile of the presentinvention is white to brown, preferably white to pale brown. The watercontent of the high purity 2-naphthylacetonitrile of the presentinvention is generally not more than 2.0 wt %, preferably not more than1.5 wt %, more preferably not more than 1.0 wt %.

In the production process of the high purity 2-naphthylacetonitrile ofthe present invention, sulfur and an organic solvent are used, but thecontents thereof are also small. The sulfur content of the high purity2-naphthylacetonitrile of the present invention is generally not morethan 0.5 area %, preferably not more than 0.3 area %, more preferablynot more than 0.1 area %, particularly preferably not more than 0.05area %. The content of an organic solvent such as sulfolane, toluene orthe like is generally not more than 0.5 wt %, preferably not more than0.3 wt %, more preferably not more than 0.1 wt %, particularlypreferably not more than 0.05 wt %.

As described above, the high purity 2-naphthylacetonitrile of thepresent invention has high HPLC purity of not less than 95 area %, morepreferably not less than 98 area %, and a lower impurity content thanthat of 2-naphthylacetonitrile produced by a conventionally-knownmethod. Thus, when it is used as a starting material or intermediate forthe synthesis of pharmaceutical products, high reactivity is expected.In addition, the high purity 2-naphthylacetonitrile of the presentinvention is excellent in solubility, and shows high dissolution ratesin organic solvents. Therefore, the high purity 2-naphthylacetonitrileof the present invention is useful as a starting material orintermediate for the synthesis of pharmaceutical products to be producedindustrially in large amounts.

Production Method of the High Purity 2-Naphthylacetonitrile of thePresent Invention

The production method of the high purity 2-naphthylacetonitrile of thepresent invention includes a step of obtaining 2-naphthylacetic acidrepresented by the following formula (3) from 2′-acetonaphthonerepresented by the following formula (2) (step 1), and a step ofobtaining 2-naphthylacetonitrile represented by the following formula(1) from 2-naphthylacetic acid (step 2).

<<Step 1>>

In step 1, 2′-acetonaphthone represented by the formula (2) is subjectedto a Willgerodt reaction, and the obtained compound is hydrolyzed togive 2-naphthylacetic acid represented by the formula (3).

In the present specification, the Willgerodt reaction means a Willgerodtreaction and a Willgerodt-Kindler reaction.

[Willgerodt Reaction]

The Willgerodt reaction can be performed by reacting 2′-acetonaphthonewith a sulfur compound such as sodium sulfide (Na₂S.9H₂O), ammoniumsulfide ((NH₄)₂S) and the like under heating.

[Willgerodt-Kindler Reaction]

The Willgerodt-Kindler reaction can be performed by reacting2′-acetonaphthone with sulfur and secondary amine such as dialkylamine,morpholine and the like under heating.

<Starting Materials>

(2′-acetonaphthone)

As 2′-acetonaphthone, a commercially available one may also be used, andone obtained by a known method may also be used.

(Sulfur Compound)

As the sulfur compound, one kind may be used alone, or two or more kindsmay be used in any combination and ratio.

The amount of the sulfur compound to be used is not particularly limitedas long as it is an amount effective for the Willgerodt reaction of2′-acetonaphthone. The amount of the sulfur compound to be used isgenerally 1 mol-5 mol, preferably 1 mol-3 mol, per 1 mol of2′-acetonaphthone.

(Sulfur)

The amount of the sulfur to be used is not particularly limited as longas it is an amount effective for reaction, and is generally 1 mol-5 mol,preferably 1 mol-3 mol, per 1 mol of 2′-acetonaphthone.

(Secondary Amine)

The secondary amine for industrial production is preferably morpholinesince reaction without solvent can be performed efficiently.

The amount of the secondary amine to be used is not particularly limitedas long as it is an amount effective for reaction. The amount of thesecondary amine to be used is generally 1 mol-6 mol, preferably 2 mol-4mol, per 1 mol of 2′-acetonaphthone.

(Solvent)

Step 1 can be performed without solvent or in an organic solvent inertto the reaction.

Examples of the organic solvent include dioxane, N,N-dimethylformamideand the like. Of these organic solvents, one kind may be used alone, ortwo or more kinds may be used in any combination and ratio. When thereaction is performed using a sulfur compound, the reaction can also beperformed in the presence of an aqueous solvent such as water and thelike.

(Additive)

In step 1, an additive may also be used as necessary.

Examples of the additive include dehydrating agents such as zeolite,molecular sieves, magnesium sulfate, sodium sulfate and the like. As thedehydrating agent, one kind may be used alone, or two or more kinds maybe used in any combination and ratio. The reaction can proceedefficiently by controlling the amount of water in the reaction system toa low level.

The amount of the dehydrating agent to be used is not particularlylimited as long as dehydration proceeds efficiently. It is generally 1mol-5 mol, preferably 1.5 mol-4 mol, per 1 mol of 2′-acetonaphthone.

Examples of the additive include organic acids such as p-toluenesulfonicacid, methanesulfonic acid, oxalic acid, trifluoroacetic acid and thelike. As the organic acid, one kind may be used alone, or two or morekinds may be used in any combination and ratio. As the organic acid,p-toluenesulfonic acid or methanesulfonic acid is particularlypreferable. Using these additives, production of by-products,particularly a ketothioamide compound represented by the followingformula

is suppressed, and the reaction can proceed efficiently.

The amount of the organic acid to be used is generally 0.01 mol-5 mol,preferably 0.05 mol-3 mol, per 1 mol of 2′-acetonaphthone.

To control the amount of water in the reaction system to a low level,the reaction may be performed while dehydrating by distillation.

<Reaction Conditions>

(Reaction Method)

While the production method of the present invention may be of a batchtype or a continuous type, it is generally of a batch type.

(Reaction Temperature)

The reaction temperature is generally 90° C.-150° C., preferably 100°C.-140° C., particularly preferably 110° C.-130° C.

(Reaction Pressure)

The reaction is generally performed under normal pressure, but may alsobe performed under pressurization.

(Reaction Time)

The reaction time can be appropriately determined according to theprogress of the reaction and is generally 1 hr-24 hr, preferably 2 hr-12hr.

<Post-Treatment>

[Hydrolysis]

The compound obtained by the Willgerodt reaction may be subjected tohydrolysis after separation from the reaction system, or may besubjected to the next hydrolysis without separation.

In the present invention, the compound obtained by the Willgerodtreaction may be hydrolyzed with a base.

(Base)

Examples of the base include alkali metal hydroxides such as sodiumhydroxide, potassium hydroxide and the like; alkaline earth metalhydroxides such as calcium hydroxide and the like; alkali metalcarbonates such as sodium carbonate, potassium carbonate and the like;alkaline earth metal carbonates such as calcium carbonate and the like;alkali metal hydrogen carbonates such as sodium hydrogen carbonate,potassium hydrogen carbonate and the like; alkaline earth metal hydrogencarbonates such as calcium hydrogen carbonate and the like; and alkalimetal alkoxides such as sodium methoxide, sodium ethoxide, potassiummethoxide, potassium ethoxide and the like. Industrially, it ispreferable to use alkali metal hydroxides such as sodium hydroxide,potassium hydroxide and the like because of the cost and availability.As the base, one kind may be used alone, or two or more kinds may beused in any combination and ratio.

The amount of the base to be used is not particularly limited as long asit is an amount effective for hydrolysis of the compound obtained afterthe Willgerodt reaction. The amount of the base to be used is generally1 mol-10 mol, preferably 1 mol-5 mol, per 1 mol of the compound obtainedafter the Willgerodt reaction.

(Solvent)

Hydrolysis may be performed without a solvent or in a solvent such aswater and the like. It is preferably performed in a solvent in view ofsuperior stirrability and uniformity.

(Reaction Temperature)

The reaction temperature of hydrolysis is not particularly limited aslong as the hydrolysis proceeds. The hydrolysis temperature is generally80° C.-115° C., preferably 85° C.-110° C.

(Reaction Pressure)

Hydrolysis is generally performed under normal pressure, but may also beperformed under pressurization.

[Liberation Reaction]

The 2-naphthylacetic acid represented by the formula (3) can beliberated by reacting a reaction product obtained by hydrolysis (e.g.,2-naphthylacetic acid or a salt thereof) with an acid.

(Acid)

For a liberation reaction of 2-naphthylacetic acid, an acid such ashydrochloric acid, sulfuric acid, hydrobromic acid or the like can beused.

As the acid, one kind may be used alone, or two or more kinds may beused in any combination and ratio. Industrially, hydrochloric acid ispreferable because of the reaction efficiency, cost and the like.

The amount of the acid to be used is not particularly limited as long asit is an amount effective for neutralization. The amount of the acid tobe used is generally 1 mol-20 mol, preferably 3 mol-10 mol, per 1 mol ofthe compound obtained by hydrolysis.

<Reaction Conditions>

(pH of Liquid)

The pH of the mixture during the liberation reaction of 2-naphthylaceticacid is generally 0-5, preferably 0-3.

(Reaction Temperature)

The temperature of the liberation reaction is not particularly limitedas long as the liberation proceeds. The temperature of the liberationreaction is generally 50° C.-90° C., preferably 60° C.-80° C.

(Reaction Time)

The reaction time is generally 10 min-5 hr, preferably 30 min-2 hr.

(Reaction Pressure)

While the reaction pressure is generally normal pressure, the reactionmay also be performed under pressurization.

(Supply Method)

As a supply method, an acid may be supplied to the reaction productobtained by hydrolysis which is placed in a reactor, or an acid isplaced in a reactor, and the reaction product obtained by hydrolysis maybe supplied, or the reaction product obtained by hydrolysis and an acidmay be supplied at the same time.

<Post-Treatment>

2-Naphthylacetic acid can be extracted and recovered using an organicsolvent from the reaction product obtained by liberation reaction.

(Organic Solvent)

Examples of the organic solvent include hydrocarbon solvents capable ofdissolving 2-naphthylacetic acid. Examples of the hydrocarbon solventinclude alicyclic hydrocarbon solvents such as cyclohexane,methylcyclohexane and the like; aromatic hydrocarbon solvents such asbenzene, toluene, xylene, mesitylene, ethylbenzene, tert-butylbenzeneand the like; and aromatic halogenated hydrocarbon solvents such astrifluoromethylbenzene, nitrobenzene, chlorobenzene, chlorotoluene,bromobenzene and the like. As the hydrocarbon solvent, alicyclichydrocarbon solvent and aromatic hydrocarbon solvent are preferable, andcyclohexane, toluene and xylene are particularly preferable, from theaspect of cost.

The hydrocarbon solvent may be used alone, or two or more kinds may beused in any combination and ratio.

The amount of the organic solvent to be used is generally 1 volumeratio-20 volume ratio, preferably 1.5 volume ratio-volume ratio,particularly preferably 3 volume ratio-5 volume ratio, with respect to2-naphthylacetic acid.

(Purification Method)

Since sulfur or sulfur compound is used in step 1, the obtained reactionproduct generally contains several mol % or more of sulfur. Sulfur is animpurity for 2-naphthylacetic acid which is the target product ofstep 1. When a chemical reaction or the like is performed using the2-naphthylacetic acid as a starting material, sulfur may decrease thereaction efficiency. Accordingly, it is preferable to remove sulfur asmuch as possible.

In the present invention, the sulfur content of the 2-naphthylaceticacid obtained in step 1 can be decreased by contacting the reactionproduct obtained by hydrolysis with a hydrocarbon solvent after theaforementioned hydrolysis, performing the aforementioned liberation inthe presence of a hydrocarbon solvent, or contacting the reactionproduct obtained by the aforementioned liberation with a hydrocarbonsolvent. Water, an aqueous solution or the like may be present asnecessary when contacting the compound with a hydrocarbon solvent. Whencontacting with a hydrocarbon solvent, the hydrocarbon solvent is usedat generally 1-30 volume ratio, preferably 3-20 volume ratio,particularly preferably 5-15 volume ratio, to the 2-naphthylacetic acid.

In the present invention, toluene is particularly preferable as theaforementioned hydrocarbon solvent because the removal of sulfur and theextraction of 2-naphthylacetic acid can be performed with a singlesolvent.

As described above, the 2-naphthylacetic acid obtained by contactingwith a hydrocarbon solvent or the like in step 1 of the presentinvention has high quality with a sulfur content of 0.001 mol %-1 mol %,preferably 0.001 mol %-0.5 mol %, and a purity of not less than 98 mol%, preferably not less than 99 mol %.

(Isolation Method)

An organic solvent capable of dissolving 2-naphthylacetic acid (e.g.,toluene, xylene, cyclohexane, etc.) is added to the reaction productobtained by the liberation reaction, the mixture is washed once orplural times with an appropriate washing solution such as water, anaqueous solution or the like, and 2-naphthylacetic acid may be isolatedusing a known method. For example, the mixture is stirred under acidicconditions (e.g., not more than pH3) with heating (e.g., 50° C.-90° C.),and washed, and the aqueous layer is separated, concentrated, and thelike as necessary and cooled, whereby 2-naphthylacetic acid can beprecipitated and recovered as a solid.

The 2-naphthylacetic acid obtained in step 1 is useful as a startingmaterial for synthesis, or an intermediate for synthesis of variousindustrial products, pharmaceutical products and the like, and can besubjected to step 2 of the present invention.

<<Step 2>>

wherein X is a halogen atom.

In step 2, 2-naphthylacetonitrile represented by the formula (1) isobtained by the following two reactions I and II.

reaction I: A reaction in which 2-naphthylacetic acid represented by theformula (4) and a halogenating agent are mixed in a first organicsolvent in the presence of a catalyst where necessary to give reactionstarting material 1 containing a compound represented by the formula(5).reaction II: A reaction in which reaction starting material 1 containinga compound represented by the formula (5) is mixed with reactionstarting material 2 containing sulfamide and a second organic solvent togive 2-naphthylacetonitrile.[Reaction I]

A reaction in which 2-naphthylacetic acid represented by the formula (3)and a halogenating agent are mixed in the first organic solvent in thepresence of a catalyst where necessary to give reaction startingmaterial 1 containing a compound represented by the formula (5).

wherein X is a halogen atom.<Starting Material>(2-naphthylacetic Acid)

As 2-naphthylacetic acid, one obtained in the aforementioned step 1 or acommercially available one can be used.

(Halogenating Agent)

The halogenating agent is not particularly limited as long as it canhalogenate 2-naphthylacetic acid. As the halogenating agent, achlorinating agent and a brominating agent are preferable, and achlorinating agent is more preferable.

Examples of the chlorinating agent include thionyl chloride, oxalylchloride, sulfuryl chloride, phosphoryl chloride, phosphorustrichloride, phosphorus pentachloride and the like.

Examples of the brominating agent include thionyl bromide, phosphorustribromide and the like.

Among these, thionyl chloride, phosphoryl chloride, phosphoruspentachloride, thionyl bromide, and phosphorus tribromide arepreferable, and thionyl chloride is particularly preferable, from theaspects of cost, broad utility, reactivity, and the like. As thehalogenating agent, one kind may be used alone, or two or more kinds maybe used in any combination and ratio.

The amount of the halogenating agent to be used is not particularlylimited as long as it is an amount at which 2-naphthylacetic acid can behalogenated. For sufficient halogenation of the 2-naphthylacetic acid,generally, not less than 1 mol of the halogenating agent is preferablyused per 1 mol of the 2-naphthylacetic acid.

While the upper limit is not particularly set on the amount to be used,not more than 3 mol per 1 mol of the 2-naphthylacetic acid is preferablefrom the aspects of cost, productivity and the like.

(Catalyst)

Reaction I can be performed in the presence of a catalyst wherenecessary. The catalyst is not particularly limited as long as itpromotes the reaction. To enhance reactivity, reaction I is preferablyperformed in the presence of a catalyst.

Examples of the catalyst include tertiary amides such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone andthe like. N,N-Dimethylformamide is particularly preferable since it iseasily available and inexpensive.

The amount of the catalyst to be used is not particularly limited aslong as it is an amount effective for functioning as a catalyst. Theamount of the catalyst to be used is preferably 0.0001 mol-1 mol, morepreferably 0.001 mol-0.1 mol, per 1 mol of the 2-naphthylacetic acid.

(First Organic Solvent)

The first organic solvent is not particularly limited as long as thereaction proceeds.

Examples of the first organic solvent include a hydrocarbon solvent, anamide solvent, a sulfoxide solvent, and a sulfone solvent. As theseorganic solvents, one kind may be used alone, or two or more kinds maybe used in any combination and ratio.

As the hydrocarbon solvent, chain aliphatic hydrocarbons such as hexane,heptane and the like; cyclic aliphatic hydrocarbons such as cyclohexane,methylcyclohexane, cycloheptane and the like; aromatic hydrocarbons suchas benzene, toluene, xylene, mesitylene, ethylbenzene, tert-butylbenzeneand the like; or aromatic halogenated hydrocarbons such astrifluoromethylbenzene, nitrobenzene, chlorobenzene, chlorotoluene,bromobenzene and the like can be used.

As the amide solvent, aprotic amides such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidinone and the like can be used.Preferred is N,N-dimethylformamide.

As the sulfoxide solvent, aprotic sulfoxides such as dimethyl sulfoxideand the like can be used.

As the sulfone solvent, aprotic sulfones such as ethyl methyl sulfone,ethyl isopropyl sulfone, 3-methylsulfolane, sulfolane and the like canbe used. Preferred is sulfolane.

In view of the superiority in operability, productivity and the like,and cost and the like, the first organic solvent is preferably ahydrocarbon solvent, an amide solvent, or a sulfone solvent, morepreferably a hydrocarbon solvent or an amide solvent, among whichtoluene, xylene, chlorobenzene and N,N-dimethylformamide are morepreferred, and toluene is particularly preferred.

Furthermore, in view of the superiority in reactivity, operability,productivity and the like, and cost and the like, a mixture of ahydrocarbon solvent and an amide solvent is also preferably used as thefirst organic solvent, and a mixture of toluene andN,N-dimethylformamide is particularly preferred. The mixing ratio(volume ratio) of the hydrocarbon solvent and the amide solvent can beappropriately selected from the range of 1:99-99:1.

The amount of the first organic solvent to be used is generally not lessthan 1 L, preferably not less than 2 L, further preferably not less than3 L, per 1 kg of the 2-naphthylacetic acid, from the aspects ofoperability and the like, and the upper limit is generally not more than50 L, preferably not more than 30 L, more preferably not more than 20 L,further preferably not more than 10 L, particularly preferably not morethan 4.5 L, most preferably not more than 4 L, per 1 kg of the2-naphthylacetic acid, from the aspects of the operability,productivity, cost and the like.

(Inorganic Additive)

In the reaction I, where necessary, an inorganic additive (e.g.,diatomaceous earth, silicic anhydride, silicon dioxide, sodium sulfate,magnesium sulfate, sodium chloride, magnesium chloride, calciumcarbonate, magnesium carbonate, etc.) may be added. Using an inorganicadditive, the reaction can proceed smoothly.

<Reaction Conditions>

(Reaction Temperature)

The reaction temperature is generally 15° C.-70° C., preferably 20°C.-65° C., particularly preferably 30° C.-60° C. When the reactiontemperature is too low, the progress of the reaction may be delayed andthe productivity may decrease, and when it is too high, by-products maybe produced and the quality may decrease.

(Reaction Time)

The reaction time is generally 0.5 hr-30 hr, preferably 1 hr-15 hr,particularly preferably 2 hr-10 hr.

(Reaction Pressure)

While the reaction pressure is generally normal pressure, the reactionmay also be performed under pressurization.

<Post-Treatment>

When the reaction mixture obtained in reaction I which contains acompound represented by the formula (5) is used for reaction II, thereaction mixture may be used as it is, or a concentrated liquid obtainedby concentrating the reaction mixture may be used, or an organic layerobtained by neutralizing the reaction mixture by mixing water or analkaline aqueous solution and separating the layer may be used.Alternatively, a poor solvent may be added to the organic layer forcrystallization, and crystals obtained by a treatment such as filtrationand the like may also be used. Furthermore, the product obtained inreaction I may be purified by a known purification means such as columnchromatography and the like. In the production method of the presentinvention, the reaction mixture or the concentrated liquid is preferablyused as it is for reaction II from the aspects of cost and productivity.

[Reaction II]

A reaction in which a compound represented by the formula (5), sulfamideand the second organic solvent are mixed to give 2-naphthylacetonitrilerepresented by the formula (1).

wherein X is a halogen atom.

This reaction II can suppress production of the naphthalene compounds(by-products) explained in the aforementioned “high purity2-naphthylacetonitrile of the present invention”.

<Starting Material>

(Compound Represented by the Formula (5))

As the compound represented by the formula (5), one obtained in reactionI can be used. It is preferable to use a concentrated liquid obtained byconcentrating the reaction mixture obtained in reaction I from theaspect of producibility.

(Sulfamide)

As sulfamide, a commercially available product can be used.

The amount of the sulfamide to be used is generally preferably not lessthan 1 mol per 1 mol of 2-naphthylacetic acid. The amount of thesulfamide to be used is generally 1 mol-5 mol, preferably 1.02 mol-3mol, more preferably 1.03 mol-2 mol, particularly preferably 1.05mol-1.5 mol, per 1 mol of 2-naphthylacetic acid.

(Second Organic Solvent)

As the second organic solvent, the same organic solvent as theaforementioned first organic solvent can be used, and a sulfone solventis preferable. From the aspects of reactivity, productivity and thelike, sulfolane is preferred.

Furthermore, as the second organic solvent, a mixture of a hydrocarbonsolvent and a sulfone solvent is also preferably used, and a mixture oftoluene and sulfolane is particularly preferable. The mixing ratio(volume ratio) of the hydrocarbon solvent and the sulfone solvent can beappropriately selected within the range of 1:99-99:1.

The amount of the second organic solvent to be used is generally notless than 1 L, preferably not less than 2 L, further preferably not lessthan 3 L, per 1 kg of the 2-naphthylacetic acid, from the aspects ofoperability and the like, and the upper limit is generally not more than50 L, preferably not more than 30 L, more preferably not more than 20 L,further preferably not more than 4.5 L, particularly preferably not morethan 4 L, per 1 kg of the 2-naphthylacetic acid, from the aspects of theoperability, productivity, cost and the like.

(Inorganic Additive)

In the reaction II, where necessary, an inorganic additive (e.g.,diatomaceous earth, silicic anhydride, silicon dioxide, sodium sulfate,magnesium sulfate, sodium chloride, magnesium chloride, calciumcarbonate, magnesium carbonate, etc.) may be added. Using an inorganicadditive, the reaction can proceed smoothly.

<Reaction Conditions>

(Reaction Temperature)

The reaction temperature may vary depending on the organic solvent,catalyst and the like to be used. The lower limit is generally not lessthan 80° C., preferably not less than 85° C., particularly preferablynot less than 90° C., from the aspects of quality, reactivity and thelike. The upper limit is generally not more than 180° C., preferably notmore than 150° C., further preferably not more than 120° C.,particularly preferably not more than 110° C., from the aspects ofquality, reactivity, cost and the like.

When the reaction temperature is too low, the progress of the reactionmay be delayed and the productivity may decrease, and when it is toohigh, by-products may be produced and the yield and quality of2-naphthylacetonitrile of a target compound may decrease.

In this embodiment, the reaction starting material 1 and the reactionstarting material 2 may be mixed and the mixture may be heated andreacted at 80° C.-180° C., or the reaction starting material 1 at 80°C.-180° C. and the reaction starting material 2 at 80° C.-180° C. may bemixed and reacted. The reaction starting material 2 may be added to thereaction starting material 1 and mixed, or the reaction startingmaterial 1 may be added to the reaction starting material 2 and mixed.

(Reaction Time)

The time of reaction of the reaction starting material 1 and thereaction starting material 2 may vary depending on the halogenatingagent, organic solvent, catalyst and the like to be used, and can beappropriately determined according to the progress of the reaction. Itis generally 0.5 hr-48 hr, preferably 1 hr-24 hr, particularlypreferably 2 hr-12 hr. When the reaction proceeds from the start ofmixing, the reaction time means the time from the start of mixing of thereaction starting material 1 and the reaction starting material 2 to thepost-treatment.

(Reaction Pressure)

The reaction is generally performed under normal pressure, but may alsobe performed under pressurization.

(Reaction Method)

While the production method of the present invention may be of a batchtype or a continuous type, it is generally of a batch type.

(Order of Supply)

The order of supply of the reaction starting material 1 and the reactionstarting material 2 can be appropriately selected. For example, thereaction starting material 1 may be placed in a reactor, and thereaction starting material 2 may be supplied and mixed, or the reactionstarting material 2 may be placed in a reactor, and the reactionstarting material 1 may be supplied and mixed, or the reaction startingmaterials 1 and 2 may be supplied at the same time into a reactor andmixed.

By making the temperature of the mixture of the reaction startingmaterial 1 and the reaction starting material 2 relatively low withrespect to the reaction temperature, the production of by-products dueto overreaction is suppressed, and higher purity 2-naphthylacetonitrilecan be produced efficiently at a low cost even in mass synthesis on anindustrial scale.

(Supply Method)

The supply method includes, for example, a method of adding the entireamount of the reaction starting material 1 to the reaction startingmaterial 2 at once, a method of dividing the reaction starting material1 into two or more and adding the two or more portions at timeintervals, a method of adding a given amount intermittently orcontinuously by dropwise addition and the like, and the like.

In the present invention, a method of dividing into two or more andadding them, and a method of adding a given amount intermittently orcontinuously by dropwise addition and the like are preferable tosuppress formation of by-products. In this case, the reaction startingmaterial 1 is added to the reaction starting material 2 such that theamount of the acid halide compound represented by the aforementionedformula (5) contained in the reaction starting material 1 (additionamount per min) is not less than 0.0027 mol/min, preferably not lessthan 0.0035 mol/min, particularly preferably not less than 0.0069mol/min, per 1 mol of sulfamide contained in the reaction startingmaterial 2. By setting the addition amount to not less than 0.0027mol/min, the amount of the acid halide compound represented by theaforementioned formula (5) in the reaction mixture of the reactionstarting material 1 and the reaction starting material 2 can be set toan appropriate range, and it is considered that formation of by-productscan be suppressed. Particularly, it is considered that the production ofa naphthalene compound represented by the formula (c) can be suppressed.

In this case, the time for adding the reaction starting material 1 tothe reaction starting material 2 can be appropriately selected accordingto the addition amount of the above-mentioned reaction startingmaterial 1. It is generally not less than 5 min, preferably not lessthan 10 min.

When the addition amount is less than 0.0027 mol/min, the production ofby-products may increase. Furthermore, when the addition time is tooshort, a large amount of gas produced as a by-product due to thereaction between the reaction starting material 1 and the reactionstarting material 2 may be rapidly generated.

(Temperature of Mixture)

The temperature of the mixture obtained by mixing the reaction startingmaterial 1 and the reaction starting material 2 may vary depending onthe organic solvent, catalyst and the like to be used. The lower limitis generally not less than 10° C., preferably not less than 15° C.,particularly preferably not less than 20° C., from the aspects ofquality, reactivity and the like. The upper limit is generally not morethan 100° C., preferably not more than 95° C., particularly preferablynot more than 90° C., from the aspects of quality, reactivity, cost andthe like.

When the temperature of the mixture obtained by mixing the reactionstarting material 1 and the reaction starting material 2 is less than15° C., the mixing may be insufficient and the reaction efficiency maydecrease. When it is higher than 90° C., the production of by-productsmay increase. Particularly, when the temperature of the mixture is high,a compound represented by the formula (5) reacts with the reactionproduct, and impurities such as the compound represented by the formula(c) and the like are easily produced. Thus, the yield and quality of2-naphthylacetonitrile represented by the formula (1) may decrease.

<Post-Treatment>

The reaction mixture containing 2-naphthylacetonitrile obtained in theaforementioned step 2 may be subjected to treatments such asneutralization, partitioning, filtration and the like, or the desired2-naphthylacetonitrile may be isolated by isolation means such asconcentration, crystallization with an organic solvent such as toluene,heptane or the like, and the like. In addition, the desired nitrilecompound can be precipitated as crystals by adding a poor solvent suchas water and the like to a reaction mixture containing the2-naphthylacetonitrile.

For example, the obtained reaction mixture is cooled, an organic solventsuch as toluene and the like is added, the organic layer is washed withwater and a base, the organic layer obtained by washing is concentrated,an organic solvent such as methanol and the like is added to theconcentrated residue for solvent substitution, the mixture is cooled,the precipitated 2-naphthylacetonitrile is collected by filtration, andthe obtained wet crystals are dried, whereby 2-naphthylacetonitrile canbe obtained as a solid.

The 2-naphthylacetonitrile obtained in the present invention has a highquality of purity (HPLC) of preferably not less than 98 area %,particularly preferably not less than 99 area %. It may be furtherpurified by a known purification means such as recrystallization, columnchromatography, activated carbon treatment and the like.

In addition, each compound in the present invention may form a solvatesuch as hydrate, organic solvent solvate, and the like, and the formthereof is not particularly limited as long as the reaction is notinhibited.

In the production method of the present invention, the following stepsare particularly preferable as step 1 and step 2.

step 1: a step of reacting 2′-acetonaphthone, sulfur and morpholine,followed by hydrolysis to give 2-naphthylacetic acid

step 2: a step of mixing a reaction starting material 1 which is amixture of 2-naphthylacetic acid, thionyl chloride, toluene and, wherenecessary, a catalyst with a reaction starting material 2 which is amixture of sulfamide and sulfolane at 15° C.-90° C., raising thetemperature and reacting the mixture at 80° C.-180° C. to give2-naphthylacetonitrile, or a step of adding the above-mentioned reactionstarting material 1 to the above-mentioned reaction starting material 2,and reacting the mixture at 80° C.-180° C. to give2-naphthylacetonitrile, wherein the reaction starting material 1 isadded to the reaction starting material 2 such that the amount of anacid chloride contained in the reaction starting material 1 is not lessthan 0.0027 mol/min per 1 mol of sulfamide contained in the reactionstarting material 2.

This step 2 can suppress production of the naphthalene compounds(by-products), particularly the naphthalene compound represented by theformula (c), explained in the aforementioned “high purity2-naphthylacetonitrile of the present invention”.

EXAMPLES

The present invention is described in more detail with reference toExamples; however, the present invention is not limited by theseexamples.

In the following Examples and Comparative Examples, commerciallyavailable 2′-acetonaphthone was used. The purity of the obtainedcompound was measured by HPLC under the following analysis conditions.

(HPLC Analysis Conditions)

analysis instrument: HPLC (1200 series) manufactured by Agilent

column: Zorbax Eclipse Plus Phenyl-Hexyl, 5 μm, 250 mm×4.6 mm

mobile phase A: 0.1 volume % trifluoroacetic acid aqueous solution

mobile phase B: acetonitrile

gradient: 0 min (B:30%)-15 min (B:60%)-20 min (B:95%)-30 min (B:95%)

flow rate: 1.0 mL/min

injection volume: 5 μL

detection wavelength: 280 nm

column temperature: 40° C.

Example 1 (1) Synthesis of 2-naphthylacetic Acid

In a nitrogen-substituted reactor were placed 2′-acetonaphthone (24 kg),sulfur (5.65 kg) (1.25 mole ratio to 2′-acetonaphthone),p-toluenesulfonic acid monohydrate (2.68 kg) (0.1 mole ratio to2′-acetonaphthone) and morpholine 36.9 kg (3 mole ratio to2′-acetonaphthone), and the mixture was stirred and reacted at 115°C.-120° C. for 3 hr. Here, the production of the thioamide compound wasconfirmed by HPLC.

The reaction mixture was cooled to 70° C.-80° C., sodium hydroxideaqueous solution at concentration 20 wt % (mixture of sodium hydroxide(16.9 kg) and water (67.7 kg), sodium hydroxide at 5 mole ratio to2′-acetonaphthone) was added, water (43.2 kg) was further added, and themixture was heated and reacted at 90° C.-105° C. for 4 hr (hydrolysis).

The obtained reaction mixture was cooled to 65° C.-75° C., water (24 kg)and toluene (83.2 kg) were added, the mixture was stirred at 65° C.-75°C. and allowed to stand, and the obtained upper layer was discarded(removal of unreacted sulfur). The remaining lower layer (206.35 kg) wasadded to a mixture of toluene (208.05 kg) and hydrochloric acid (80.8kg) at a concentration of 35 wt %. The reactor that contained the lowerlayer was washed with water (2.4 kg). The liquid obtained after washingwas also added to the aforementioned mixture. A mixture containing thethus-obtained reaction mixture was stirred at 65° C.-75° C., and allowedto stand (extraction of 2-naphthylacetic acid), and the obtained lowerlayer was discarded. To the remaining upper layer was added water (121.0kg), and the mixture was stirred at 65° C.-75° C. and allowed to stand,and the lower layer was discarded. To the remaining upper layer wasadded water (121 kg), and the mixture was stirred at 65° C.-75° C. andallowed to stand, and the lower layer was discarded.

The remaining upper layer was concentrated and cooled to not more than10° C. The precipitated crystals of 2-naphthylacetic acid were collectedby centrifugation and washed with toluene (20.8 kg) to give wetcrystals. The obtained wet crystals were dried under reduced pressureunder temperature condition at 60° C. to give 2-naphthylacetic acid(19.70 kg). ¹H-NMR (400 MHz, CDCl₃) δ 3.80 (2H, s), 7.40 (1H, dd, J=8.4,3.0 Hz), 7.43-7.49 (2H, m), 7.73 (1H, s), 7.78-7.82 (3H, m)

(2) Synthesis of 2-naphthylacetonitrile

In a nitrogen-substituted reactor were added 2-naphthylacetic acid (18.7kg) obtained in the above-mentioned (1), toluene (40.55 kg), andN,N-dimethylformamide (73.08 g). The instrument used for theabove-mentioned addition was washed with toluene (16.2 kg) and theliquid obtained after washing was also added to the reactor. To theobtained solution was added thionyl chloride (12.5 kg) (1.05 mole ratioto 2-naphthylacetic acid), and the mixture was reacted at 35° C.-45° C.for 5 hr. After cooling to 20° C.-30° C., the mixture was filtered. Theobtained filtrate was mixed with a washing obtained by washing thefiltration residue with toluene (8.15 kg), sulfolane (23.6 kg) (1 volumeratio to 2-naphthylacetic acid) was added, and the mixture wasconcentrated under reduced pressure to prepare an acid chloridesolution.

In another nitrogen-substituted reactor were placed sulfamide (11.6 kg)(1.2 mole ratio to 2-naphthylacetic acid), sulfolane (58.9 kg) (2.5volume ratio to 2-naphthylacetic acid) and an inorganic additive (18.7kg), and the mixture was stirred and heated to 95° C.-105° C. to preparea sulfamide solution.

The acid chloride solution was added dropwise to the sulfamide solutionover 2 hr at 95° C.-105° C. The reactor that contained the acid chloridesolution was washed with toluene (1.62 kg). The liquid obtained afterwashing was also added to the reactor, and the mixture was reacted at95° C.-105° C. for 7 hr.

The obtained reaction mixture was cooled to 25° C., toluene (65 kg) andwater (74.8 kg) were added, the mixture was stirred at 20° C.-30° C. andallowed to stand, and the lower layer was discarded. To the remainingupper layer were added water (35.5 kg) and potassium carbonate (5.61kg). The instrument used for the above-mentioned reaction was washedwith water (15 kg) and the liquid obtained after washing was also addedto a mixture containing the above-mentioned upper layer. The obtainedmixture was stirred at 20° C.-30° C. and allowed to stand, and the lowerlayer was discarded. To the remaining upper layer was added water (37.4kg), the mixture was stirred at 20° C.-30° C. and allowed to stand, andthe lower layer was discarded. The remaining upper layer wasconcentrated, methanol (104 kg) was added, and the mixture was furtherconcentrated. To the obtained concentrated liquid was added methanol(44.4 kg), and the mixture was concentrated. To the obtainedconcentrated liquid were added activated carbon (0.374 kg) and methanol(45.1 kg) at 35° C., and the mixture was stirred and filtered. Thefiltration residue was washed with methanol (14.95 kg), and the filtrateand the liquid after washing were mixed.

The obtained mixed solution was maintained at 30° C.-40° C. for about 90min and cooled, water (74.8 kg) (4 volume ratio to 2-naphthylaceticacid) was added at a temperature near 10° C., and the mixture wasstirred for 4 hr. The precipitated crystals were collected bycentrifugation, and the collected wet crystals were washed with amethanol aqueous solution (mixed solution of methanol (14.8 kg) andwater (18.7 kg)). The obtained wet crystals were dried under reducedpressure under temperature condition at 60° C. to give2-naphthylacetonitrile as crystals (15.2 kg, purity 99.50 area %).

¹H-NMR (400 MHz, CDCl₃) δ 3.92 (2H, s), 7.37-7.40 (1H, m), 7.49-7.54(2H, m), 7.83-7.85 (4H, m)

The HPLC analysis results of the obtained 2-naphthylacetonitrile areshown in Table 3 and FIG. 1 . In Table 3, RRT is a relative retentiontime when the retention time of 2-naphthylacetonitrile is 1.00.

TABLE 3 content compound RRT (area %) 2-naphthylacetonitrile 1.00 99.50impurities compound of the 1.09 0.20 formula (a) compound of the 1.230.06 formula (b) compound of the 1.39 0.15 formula (c) compound of the1.63 0.02 formula (d) other impurity — 0.07

From the HPLC analysis results, the compounds of the formulas (e)-(j)were not detected in the obtained 2-naphthylacetonitrile.

The ¹H-NMR measurement results of the compounds of the formulas (a)-(d)are as follows.

¹H-NMR (400 MHz, CDCl₃) δ=3.71 (s, 3H), 3.79 (s, 2H), 7.40-7.47 (m, 3H),7.73 (s, 1H), 7.79-7.83 (m, 3H)

LC/MS 215 (m/z, Pos)

¹H-NMR (400 MHz, CDCl₃) δ=1.26 (t, J=7.2 Hz, 3H), 3.78 (s, 2H), 4.17 (q,J=7.2 Hz, 2H), 7.41-7.49 (m, 3H), 7.74 (s, 1H), 7.79-7.82 (m, 3H)

LC/MS 354 (m/z, Pos)

¹H-NMR (400 MHz, dmso-d₆) δ=4.03 (s, 4H), 7.41 (dd, J=8.4, 1.6 Hz, 2H),7.48-7.50 (m, 4H), 7.75 (s, 2H), 7.82-7.90 (m, 6H), 11.12 (s, 1H)

LC/MS 503 (m/z, Pos)

¹H-NMR (400 MHz, CDCl₃) δ=1.27 (s, 9H), 3.54 (s, 2H), 3.59 (s, 2H), 7.04(d, J=8.8 Hz, 1H), 7.11 (d, J=2.0 Hz, 1H), 7.21 (dd, J=8.4, 2.4 Hz, 1H),7.29-7.34 (m, 2H), 7.42-7.49 (m, 4H), 7.59 (s, 1H), 7.63 (s, 1H),7.76-7.79 (m, 6H)

Example 2

In a nitrogen-substituted reactor were added 2-naphthylacetic acid(75.02 g) synthesized according to the method of Example 1(1), toluene(263 mL) (3.5 volume ratio to 2-naphthylacetic acid), andN,N-dimethylformamide (0.29 g) (0.01 mole ratio to 2-naphthylaceticacid), the mixture was heated, and thionyl chloride (50.3 g) (1.05 moleratio to 2-naphthylacetic acid) was added at 35° C.-45° C. Afterreaction for 3 hr, the reaction mixture was concentrated and reactionstarting material 1 containing 2-naphthylacetyl chloride was prepared.

In another nitrogen-substituted reactor were added sulfamide (46.49 g)(1.2 mole ratio to 2-naphthylacetic acid), an inorganic additive (74.99g) (1 weight ratio to 2-naphthylacetic acid), and sulfolane (263 mL)(3.5 volume ratio to 2-naphthylacetic acid), and the mixture was heated(preparation of reaction starting material 2). The reaction startingmaterial 1 containing 2-naphthylacetyl chloride was added dropwise tothe reaction starting material 2 at 95° C.-105° over 18 min. Theinstrument used for preparing the reaction starting material 1 waswashed with toluene (7.5 mL) (0.1 volume ratio to 2-naphthylaceticacid), the obtained solution was further added to the reaction startingmaterial 2, and the mixture was reacted at 95° C.-105° C. for 4 hr. Thereaction mixture was analyzed by HPLC, and the disappearance of thestarting materials was confirmed. Then, the mixture was cooled to 20°C.-30° C., water (300 mL) (4 volume ratio to 2-naphthylacetic acid) andtoluene (300 mL) (4 volume ratio to 2-naphthylacetic acid) were added,the mixture was stirred, and the aqueous layer was discarded. Theremaining organic layer was washed with 10 wt % potassium carbonateaqueous solution (225.08 g) (3 weight ratio to 2-naphthylacetic acid)and water (150 mL) (2 volume ratio to 2-naphthylacetic acid).

The obtained organic layer was concentrated, methanol (525 mL) (7 volumeratio to 2-naphthylacetic acid) was added to the concentrated residue,and the mixture was concentrated again. Furthermore, methanol was addedto the obtained concentrated residue to adjust the liquid amount to 525mL. Activated carbon (1.52 g) (0.02 weight ratio to 2-naphthylaceticacid) was added, and the mixture was stirred at 50° C.-60° C. andfiltered. The obtained filtration residue was washed with methanol (75mL) (1 volume ratio to 2-naphthylacetic acid).

The obtained filtrate and washing solution were cooled to 5° C.-15° C.,water (300 mL) (4 volume ratio to 2-naphthylacetic acid) was added, andthe mixture was stirred. The precipitated 2-naphthylacetonitrile wascollected by filtration, and the obtained wet crystals were dried toobtain 2-naphthylacetonitrile (60.38 g) (purity 99.85 area %) as asolid.

The HPLC analysis results of the reaction mixture after reaction for 4hr and the obtained 2-naphthylacetonitrile are shown in Table 4.

TABLE 4 reaction mixture after reaction for 4 hr crystal compound RRT(area %) (area %) 2-naphthylacetonitrile 1.00 96.50  99.85 impuritiescompound of the 1.08 not 0.04 formula (a) detected compound of the 1.220.87 0.05 formula (b) compound of the 1.35 0.15 0.06 formula (c) otherimpurity — 2.48 not detected

From the HPLC analysis results, the compounds of the formulas (d)-(j)were not detected in the obtained crystal of 2-naphthylacetonitrile.

Example 3

In a nitrogen-substituted reactor were added 2-naphthylacetic acid (25g) synthesized according to the method of Example 1(1), toluene (75.88g) (3.5 volume ratio to 2-naphthylacetic acid), andN,N-dimethylformamide (0.0982 g) (0.01 mole ratio to 2-naphthylaceticacid). To the obtained solution was added dropwise thionyl chloride(16.77 g) (1.05 mole ratio to 2-naphthylacetic acid), and the mixturewas reacted at 43° C.-45° C. for 3 hr. Toluene (10.88 g) (0.5 volumeratio to 2-naphthylacetic acid) and sulfolane (31.53 g) (1 volume ratioto 2-naphthylacetic acid) were added, and the mixture was concentratedunder reduced pressure to prepare reaction starting material 1containing 2-naphthylacetyl chloride.

In another nitrogen-substituted reactor were added sulfamide (15.5 g)(1.2 mole ratio to 2-naphthylacetic acid), sulfolane (78.78 g) (2.5volume ratio to 2-naphthylacetic acid), and an inorganic additive (25.01g), and the mixture was stirred and heated to 75° C.-85° C. (preparationof reaction starting material 2). The reaction starting material 2 wasnot a solution but a slurry.

The reaction starting material 1 containing 2-naphthylacetyl chloridewas added dropwise to the reaction starting material 2 at 75° C.-85°over 10 hr, and the mixture was heated to 100° C. over 2 hr and reactedfor 5 hr.

The obtained reaction mixture was cooled to 55° C.-65° C., toluene (86.7g) (4 volume ratio to 2-naphthylacetic acid) and water (100.05 g) (4volume ratio to 2-naphthylacetic acid) were added. The mixture wasstirred and allowed to stand, and the lower layer was discarded. To theremaining upper layer was added 5 wt % aqueous sodium hydrogen carbonatesolution (75.01 g) (3 weight ratio to 2-naphthylacetic acid). Themixture was stirred at 55° C.-65° C. and allowed to stand, and the lowerlayer was discarded. To the remaining upper layer was added water (50.01g) (2 weight ratio to 2-naphthylacetic acid), the mixture was stirred at55° C.-65° C. and allowed to stand, and the lower layer was discarded.The remaining upper layer was concentrated, methanol (138.44 g) (7volume ratio to 2-naphthylacetic acid) was added to the concentratedresidue, and the mixture was further concentrated. To the obtainedconcentrated residue was added methanol (59.34 g) (3 volume ratio to2-naphthylacetic acid), and the mixture was concentrated. To theconcentrated residue were added methanol (39.55 g) (2 volume ratio to2-naphthylacetic acid) and activated carbon (0.5 g) (0.02 weight ratioto 2-naphthylacetic acid), and the mixture was filtered. The obtainedfiltrate was mixed with a washing obtained by washing the filtrationresidue with methanol (19.78 g) (1 volume ratio to 2-naphthylaceticacid) to give a 2-naphthylacetonitrile solution.

The obtained 2-naphthylacetonitrile solution was heated to 40° C.-50°C., water (0.1259 g) (0.005 volume ratio to 2-naphthylacetic acid) andpotassium carbonate (0.0248 g) (0.001 weight ratio to 2-naphthylaceticacid) were added, and the mixture was stirred for 1 hr. Water (100 g) (4volume ratio to 2-naphthylacetic acid) was added dropwise over 1 hr.Thereafter, the mixture was cooled and stirred at a temperature near 10°C. for 1 hr. The precipitated crystals were collected by filtration, andthe collected wet crystals were washed twice with a methanol aqueoussolution (mixed solution of methanol (27.71 g) and water (15.03 g)). Theobtained wet crystals were dried under reduced pressure undertemperature condition at 60° C. to give 2-naphthylacetonitrile ascrystals (19.09 g, yield 85%, purity 99.87 area %).

The HPLC analysis results of the obtained 2-naphthylacetonitrile areshown in Table 5 and FIG. 2 .

TABLE 5 content compound RRT (area %) 2-naphthylacetonitrile 1.00 99.87 impurities compound of the 1.08 0.02 formula (a) compound of the 1.39not formula (c) detected compound of the 1.63 0.02 formula (d)

From the HPLC analysis results, the compounds of the formulas (b) and(e)-(j) were not detected in the obtained crystal of2-naphthylacetonitrile. According to this Example,2-naphthylacetonitrile having a lower content of impurities, forexample, the compounds of the formula (a) and the formula (c), than inExamples 1 and 2 was obtained. In particular, the 2-naphthylacetonitrileobtained in this Example does not contain the compound of the formula(c) and is useful as a starting material or intermediate for thesynthesis of pharmaceutical products.

As described above, it is clear that high purity 2-naphthylacetonitrilewith a small content of impurities can be obtained by mixing reactionstarting material 1 containing 2-naphthylacetyl chloride and reactionstarting material 2 containing sulfamide at a comparatively lowtemperature, and heating and reacting the mixture.

Example 4

In a nitrogen-substituted reactor were added 2-naphthylacetic acid(10.03 g) synthesized according to the method of Example 1(1), toluene(35 mL) (3.5 volume ratio to 2-naphthylacetic acid), andN,N-dimethylformamide (42 μL) (0.01 mole ratio to 2-naphthylaceticacid), the mixture was heated, and thionyl chloride (6.72 g) (1.05 moleratio to 2-naphthylacetic acid) was added at 35° C.-45° C. Afterreacting for 2 hr, the mixture was cooled and filtered at roomtemperature, and the filtration residue was washed with toluene (5 mL).To the obtained filtrate and washing solution was added sulfolane (10mL) (1 volume ratio to 2-naphthylacetic acid), the mixture wasconcentrated, and reaction starting material 1 containing2-naphthylacetyl chloride was prepared.

In another nitrogen-substituted reactor were added sulfamide (6.19 g)(1.2 mole ratio to 2-naphthylacetic acid), an inorganic additive (10.01g) (1.0 weight ratio to 2-naphthylacetic acid), and sulfolane (25 mL)(2.5 volume ratio to 2-naphthylacetic acid), and the mixture was heated(preparation of reaction starting material 2). The reaction startingmaterial 1 containing 2-naphthylacetyl chloride was added dropwise tothe reaction starting material 2 at 95° C.-105° over 1 hr. Theinstrument used for preparing the reaction starting material 1 waswashed with toluene (1 mL) (0.1 volume ratio to 2-naphthylacetic acid),the obtained solution was further added, and the mixture was reacted at95° C.-105° C. for 4 hr. The reaction mixture was analyzed by HPLC. As aresult, 2-naphthylacetonitrile (96.27 area %) and the compound of theformula (c) (0.39 area %) were contained.

The reaction mixture was cooled to 25° C., water (40 mL) (4 volume ratioto 2-naphthylacetic acid) and toluene (40 mL) (4 volume ratio to2-naphthylacetic acid) were added, the mixture was stirred, and thelower layer was discarded. The remaining organic layer was washed with10 wt % potassium carbonate aqueous solution (30.32 g) (3 weight ratioto 2-naphthylacetic acid) and water (20 mL) (2 volume ratio to2-naphthylacetic acid).

The obtained organic layer was concentrated, methanol (70 mL) (7 volumeratio to 2-naphthylacetic acid) was added to the concentrated residue,and the mixture was concentrated again. Furthermore, methanol was addedto the obtained concentrated residue to adjust the liquid amount to 70mL. Activated carbon (0.2 g) (0.02 weight ratio to 2-naphthylaceticacid) was added, and the mixture was stirred at 40° C.-50° C. andfiltered. The obtained filtration residue was washed with methanol (10mL) (1 volume ratio to 2-naphthylacetic acid).

The obtained filtrate and washing solution were cooled to 5° C.-15° C.,water (40 mL) (4 volume ratio to 2-naphthylacetic acid) was added, andthe mixture was stirred. The precipitated 2-naphthylacetonitrile wascollected by filtration, and the obtained wet crystals were dried toobtain 2-naphthylacetonitrile (8.11 g) (purity 99.30 area %) as a solid.

The HPLC analysis results of the reaction mixture after reaction for 4hr and the obtained 2-naphthylacetonitrile are shown in Table 6.

TABLE 6 reaction mixture after reaction for 4 hr crystal compound RRT(area %) (area %) 2-naphthylacetonitrile 1.00 96.27  99.30  impuritiescompound of the 1.08 not 0.06 formula (a) detected compound of the 1.220.62 not formula (b) detected compound of the 1.35 0.39 0.09 formula (c)other impurity — 2.72 0.55

From the HPLC analysis results, the compounds of the formulas (d)-(j)were not detected in the obtained crystal of 2-naphthylacetonitrile.

Example 5

In the same manner as in Example 4 except that the time for dropwiseaddition of reaction starting material 1 was changed from 1 hr to 8 min,the reaction was performed.

The reaction mixture obtained by reacting reaction starting material 1and reaction starting material 2 for 4 hr was measured by HPLC. As aresult, 2-naphthylacetonitrile (95.94 area %) and the compound of theformula (c) (0.30 area %) were contained.

Example 6

In the same manner as in Example 4 except that the time for dropwiseaddition of reaction starting material 1 was changed from 1 hr to 4 hr,the reaction was performed.

The reaction mixture obtained by reacting reaction starting material 1and reaction starting material 2 for 4 hr was measured by HPLC. As aresult, 2-naphthylacetonitrile (96.37 area %) and the compound of theformula (c) (0.70 area %) were contained.

Comparative Example 1

In the same manner as in Example 4 except that the time for dropwiseaddition of reaction starting material 1 was changed from 1 hr to 10 hr,2-naphthylacetonitrile was synthesized.

The reaction mixture obtained by reacting reaction starting material 1and reaction starting material 2 for 4 hr was measured by HPLC. As aresult, 2-naphthylacetonitrile (92.75 area %) and the compound of theformula (c) (1.16 area %) were contained.

The obtained 2-naphthylacetonitrile was analyzed by HPLC. As a result,the content of 2-naphthylacetonitrile was 97.44 area %, and the contentof the compound of the formula (c) was 0.47 area %.

The dropwise addition time and the addition amount of reaction startingmaterial 1, and the contents of the 2-naphthylacetonitrile and thecompound of the formula (c) in the reaction mixture obtained by reactingfor 4 hr are shown in Table 7.

In Table 7, the addition amount of reaction starting material 1 meansthe addition amount (mol/min) of the acid chloride compound contained inreaction starting material 1 per 1 mol of sulfamide contained in thereaction starting material 2.

TABLE 7 reaction starting material 1 content in the reaction dropwiseaddition mixture (area %) addition amount 2-naphthyl- compound of time(mol/min) acetonitrile formula (c) Example 4 1 hr 0.014 96.27 0.39Example 5 8 min 0.104 95.94 0.30 Example 6 4 hr 0.0035 96.37 0.70Comparative 10 hr 0.0014 92.75 1.16 Example 1

As is clear from Table 7, a smaller amount of the compound of theformula (c) is produced when the addition amount (mol/min) of the acidchloride compound contained in the reaction starting material 1 islarger.

However, when the addition amount (mol/min) of the acid chloridecompound contained in the reaction starting material 1 is too large, alarge amount of hydrochloric acid gas as a by-product may be generated.It is thus necessary to pay attention to safety by, for example,providing a processing apparatus and the like in the case of industrialproduction of a large amount.

INDUSTRIAL APPLICABILITY

According to the present invention, high purity 2-naphthylacetonitrilewith less impurity which is useful as a starting material orintermediate for the synthesis of various pharmaceutical products,agricultural chemicals, and chemical products, particularly a startingmaterial or intermediate for the synthesis of pharmaceutical products,can be provided. In addition, a production method capable of producinghigh purity 2-naphthylacetonitrile safely, highly efficiently,industrially in a large amount at a low cost can be provided.Furthermore, using the 2-naphthylacetonitrile of the present invention,pharmaceutical products such as(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane and the like canbe produced industrially in a large amount at a low cost.

This application is based on a patent application No. 2019-196782 filedin Japan (filing date: Oct. 29, 2019), the contents of which areincorporated by reference in full herein.

The invention claimed is:
 1. A method for producing a high purity2-naphthylacetonitrile, the method comprising: mixing a first reactionstarting material comprising an acid halide compound of formula (5), inwhich X is a halogen atom

and a first organic solvent, and a second reaction starting materialcomprising sulfamide and a second organic solvent at a temperature in arange of from 15 to 90° C.; raising the temperature and reacting themixture at a temperature in a range of from 80 to 180° C. to give2-naphthylacetonitrile.
 2. The method of claim 1, wherein the firstreaction starting material is added to the second reaction startingmaterial at a temperature in a range of from 15 to 90° C.; raising thetemperature of a resulting mixture, and reacting the mixture at atemperature in a range of from 80 to 180° C.
 3. The method of claim 2,wherein the first reaction starting material is added to the secondreaction starting material such that an amount of the acid halidecompound is not less than 0.0027 mol/min per 1 mol of sulfamide.
 4. Themethod of claim 1, wherein the first reaction starting material isobtained by mixing 2-naphthylacetic acid, a halogenating agent, and thefirst organic solvent, optionally in the presence of a catalyst.
 5. Amethod for producing high purity 2-naphthylacetonitrile, the methodcomprising: subjecting 2′-acetonaphthone to a Willgerodt reaction,optionally in the presence of an additive, to obtain an amide compound;hydrolyzing the amide compound; and liberating 2-naphthylacetic acid togive 2-naphthylacetic acid; mixing and reacting a first reactionstarting material comprising the liberated 2-naphthylacetic acid, ahalogenating agent, and a first organic solvent, and a reaction startingmaterial comprising sulfamide and a second organic solvent, to give2-naphthylacetonitrile.
 6. The method of claim 1, wherein the firstorganic solvent is a hydrocarbon solvent, an amide solvent, a sulfonesolvent or a mixed solvent thereof, and the second organic solvent is asulfone solvent.